The General Impact of Haploinsufficiency on Brain Connectivity Underlies the Pleiotropic Effect of Neuropsychiatric CNVS

Moreau, Clara; Huguet, Guillaume; Urchs, Sebastian; Kumar, Kuldeep; Douard, Élise; Sharmarke, Hanad; Orban, Pierre; Linden, David; Maillard, Anne; Lippé, Sarah; Bearden, Carrie E.; Thompson, Paul M.; Bellec, Pierre; Jacquemont, Sébastien

doi:10.1016/j.biopsych.2021.02.115

Cited by 3 publications

(4 citation statements)

References 22 publications

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“…The deficits in information integration at the neural and cognitive levels found in neurodevelopmental disorders may be the results of under-functioning neural circuitry caused by the CNVs (under-connectivity theory [80,81]). Our results are also in agreement CNVs in that we found a reorganization of global connectivity irrespective of where CNVs occur in the genome, with additional precision in the spectral scale [18,19]. Previous studies also demonstrated various resting-state architectures of under-connectivity in several neurodevelopmental disorders [67,[82][83][84].…”

Section: Connectivity Characteristics Of Cnv Carrierssupporting

confidence: 90%

“…DEL vs. DUP) of recurrent CNVs was shown to be an important factor affecting the brain distinctively. For instance, DEL and DUP at the 16p11.2, 22q11.2, and 1q21.1 loci have been associated with mirror effects on global functional connectivity in fMRI [18,19]. Electroencephalography (EEG) is well suited to capture the multiple time-scales of brain processing, as it records neuronal oscillations on the millisecond scale.…”

Section: Introductionmentioning

confidence: 99%

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Genetic modulation of brain dynamics in neurodevelopmental disorders: the impact of copy number variations on resting-state EEG

Audet-Duchesne¹,

Knoth

Martin³

et al. 2023

Preprint

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Research has shown that many copy number variations (CNVs) increase the risk of neurodevelopmental disorders (e.g., autism, ADHD, schizophrenia). However, little is known about the effects of CNVs on brain development and function. Resting-state electroencephalography (EEG) is a suitable method to study the disturbances of neuronal functioning in CNVs. We aimed to determine whether there are resting-state EEG signatures that are characteristic of children with pathogenic CNVs. EEG resting-state brain activity of 109 CNVs carriers (66 deletion carriers, 43 duplication carriers) aged 3 to 17 years was recorded for 4 minutes. To better account for developmental variations, EEG indices (power spectral density and functional connectivity) were corrected with a normative model estimated from 256 Healthy Brain Network controls. Results showed increased beta and gamma power in posterior regions as well as global under-connectivity in several frequency bands in CNVs carriers. Deletion and duplication carriers can be differentiated by their connectivity in low alpha frequencies: duplication carriers connectivity was more disrupted than deletion carriers. The distinctive connectivity perturbations were found to be most prominent during adolescence. The results suggest that CNVs carriers show electrophysiological alterations compared to neurotypical controls, regardless of the gene dosage effect and of their affected genomic region. Moreover, a specific signature of the brain alterations associated with duplications was found.

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Section: Connectivity Characteristics Of Cnv Carrierssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Genetic modulation of brain dynamics in neurodevelopmental disorders: the impact of copy number variations on resting-state EEG

Audet-Duchesne¹,

Knoth

Martin³

et al. 2023

Preprint

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show abstract

“…The deletion is associated with macrocephaly, greater cortical gray matter volume and surface area, and a global increase in functional connectivity. The duplication, in contrast, is associated with microcephaly, smaller cortical gray matter volume and surface area, and a global decrease in functional connectivity (Jacquemont et al, 2011;Modenato et al, 2021;Moreau et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Motor difficulties in 16p11.2 copy number variation

Jutla,

Harvey,

Veenstra‐VanderWeele

et al. 2024

Autism Research

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The rare genetic variants 16p11.2 duplication and 16p11.2 deletion have opposing effects on brain structure and function, yet are associated with broadly similar clinical phenotypes that include autism, intellectual impairment, psychiatric illness, and motor difficulties. In recent years, studies have identified subtle distinctions between the phenotypic effects of 16p11.2 duplication and 16p11.2 deletion with respect to patterns of autism, intellectual impairment, and psychiatric illness. However, although divergent phenotypic findings in some motor domains have been reported, no study has yet made a comprehensive comparison of motor difficulties between 16p11.2 deletion and 16p11.2 duplication carriers to elucidate points of convergence and divergence. We sought to make such a comparison in a group of 133 16p11.2 deletion carriers, 122 duplication carriers, and 388 familial controls, hypothesizing that motor impairment would overall be greater in deletion than duplication carriers. In a series of regression models, we found that 16p11.2 deletion status tended to predict greater impairment along indices of gross motor function, but less impairment along indices of fine motor function. These findings point to a potential pattern of performance difficulties that could be investigated in future studies. Elucidating motor differences between 16p11.2 duplication and 16p11.2 deletion carriers may help in understanding the complex effect of 16p11.2 copy number variation and other rare genetic causes of autism.

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“…CNVs often have pleiotropic effects, influencing multiple downstream processes simultaneously (17)(18)(19). The diversity in genetic CNV-mediated effects is heightened by interactions with both the rest of the genome and environmental factors (20).…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Link between CNVs, General Cognition, and Individual Neuroimaging Deviation Scores from a Reference Cohort

Fraza,

Sønderby,

Boen

et al. 2023

Preprint

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BackgroundCopy number variations (CNVs) are genetic variants that can have substantial influence on neurodevelopment, neuropsychiatric traits and morphometric brain changes, yet their impact at the individual level remains unknown. Common case-control approaches for analyzing CNVs often overlook individual variation between carriers and exclude rarer variants, due to their limited sample size. This study aims to map individualized brain deviation scores in individuals with pathogenic CNVs.MethodsWe used normative modeling to map neuroimaging features from several large neuroimaging datasets and applied these models to understand the neurobiological profile of CNV carriers in UK Biobank. We highlighted the 1q21.1 distal deletion and duplication, as an example of our normative modeling-CNV approach. Next, we counted the number of extreme deviations for each participant from the mean and centiles of variation from population reference norms, giving us a combined risk score per participant per imaging modality.ResultsWe show a high degree of heterogeneity between pathogenic CNV carriers in their implicated brain regions. For example, the cerebellum, brainstem and the pallidum show large negative deviations for certain 1q21.1 duplication carriers. For certain 1q21.1 deletion CNV carriers the caudate and accumbens show notable positive deviations. Finally, we show that negative deviations from these models are correlated to cognitive function.ConclusionsThis study marks a starting point in comprehending the impact of pathogenic CNVs on brain phenotypes, underscoring the intricacies of these genetic variations at the individual level and provides a means to studying the effects of rare CNVs in carrier individuals.

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The General Impact of Haploinsufficiency on Brain Connectivity Underlies the Pleiotropic Effect of Neuropsychiatric CNVS

Cited by 3 publications

References 22 publications

Genetic modulation of brain dynamics in neurodevelopmental disorders: the impact of copy number variations on resting-state EEG

Genetic modulation of brain dynamics in neurodevelopmental disorders: the impact of copy number variations on resting-state EEG

Motor difficulties in 16p11.2 copy number variation

Unraveling the Link between CNVs, General Cognition, and Individual Neuroimaging Deviation Scores from a Reference Cohort

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